PROJECT SUMMARY/ABSTRACT Anxiety disorders (AXD) occur in up to one-third of individuals with alcohol dependence seeking treatment and are associated with poor treatment response in people who have comorbid alcohol use disorders (AUD). Despite the major personal and public health impact of this comorbidity, effective treatments have not been established and there is a lack of adequate research to guide treatment decisions. In recent work we have demonstrated that the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP; Barlow, Farchione, et al., 2011) significantly reduced heavy drinking in comorbid AUD/AXD disorders, but venlafaxine, a drug approved by the US FDA for treatment of anxiety, did not have an effect on drinking, despite decreasing anxiety and depression. In clinical trials that we conducted zonisamide (ZON) administration reduced alcohol consumption in individuals with AUD, as reflected by decreased percent days with heavy drinking; decreased drinks consumed per day, and decreased percent days with any drinking. The current proposal will examine an established transdiagnostic cognitive-behavioral intervention for emotional disorders (e.g., anxiety and mood disorders), the UP, relative to ZON, a medication that directly influences alcohol consumption without working through the mechanism of anxiety reduction. The central focus of this proposal is to examine the efficacy of UP and ZON in reducing alcohol consumption in patients with comorbid AUD/AXD, relative to a low intensity behavioral treatment control consisting of Take Control (TC), a novel form of psychotherapy for AUD that we developed in collaboration with the NIAAA, in combination with pill placebo (PLC). We propose a placebo- controlled, double-blind clinical trial with three groups: 1) UP, 2) ZON, and 3) TC+PLC. After screening, all participants will receive treatment for 16 weeks. ZON will be reduced during study weeks 17 and 18, following a post-treatment assessment, and follow-up measures will be obtained one month and six months after the post-treatment assessment. Alcohol consumption will be assessed using both ecological momentary assessment and the time-line follow back procedures. The Depression Anxiety Stress Scale, Hamilton Anxiety and Depression Rating scales, and the Anxiety Disorders Interview Schedule for DSM-5 will be used to measure anxiety and depression. Complementing these assessments are additional scales examining higher- order temperamental variables and core psychopathological mechanisms related to emotional dysregulation that have been shown to contribute to the development and maintenance of these disorders and may account for the high amount of diagnostic overlap seen clinically. Further, we will use magnetic resonance spectroscopy (MRS) to examine the effects of UP and ZON on changes in brain glutamate (Glu), GSH, and GABA levels, and analyze blood samples to measure GSH and other oxidative stress biomarkers. Using MRS to measure changes in these neurochemicals during treatment may lead to a better mechanistic understanding of UP and ZON, and possibly help optimize use of these treatments in patients with AUD.